| 1. |
- Chugh, Deepti, et al.
(författare)
-
Brain inflammation induces post-synaptic changes during early synapse formation in adult-born hippocampal neurons.
- 2013
-
Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 250, s. 176-188
-
Tidskriftsartikel (refereegranskat)abstract
- An inflammatory reaction in the brain is primarily characterized by activation of parenchymal microglial cells. Microglia regulate several aspects of adult neurogenesis, i.e. the continuous production of new neurons in the adult brain. Hippocampal neurogenesis is thought to be important for memory formation, but its role in brain diseases is not clear. We have previously shown that brain inflammation modulates the functional integration of newly formed hippocampal neurons. Here, we explored whether there is a defined time period during synaptic development when new neurons are susceptible to brain inflammation. Newly formed hippocampal neurons, born in an intact environment in the adult mouse brain, were exposed to lipopolysaccharide (LPS)-induced inflammation during either early or late phases of excitatory and inhibitory synaptogenesis. We used intra-hippocampal injections of GFP-retroviral vector (RV-GFP) to label the new neurons and ipsilateral LPS injection at either 1 or 4weeks post-RV-GFP injection. A single intra-hippocampal LPS injection induced an inflammatory response for at least 3weeks, including an acute transient pro-inflammatory cytokine release as well as a sub-acute and sustained change in microglial morphology. The general cytoarchitecture of the hippocampal dentate gyrus, including granule cell layer (GCL) volume, and astrocytic glial fibrillary acidic protein expression was not different compared to vehicle controls, and no Fluoro-Jade-positive cell death was observed. New neurons encountering this inflammatory environment exhibited no changes in their gross morphology. However, when inflammation occurred during early stages of synapse formation, we found a region-specific increase in the number of thin dendritic spines and post-synaptic density-95 (PSD-95) cluster formation on spines, suggesting an enhanced excitatory synaptic connectivity in the newborn neurons. No changes were observed in the expression of N-cadherin, an adhesion molecule primarily associated with excitatory synapses. At the inhibitory synapses, alterations due to inflammation were also evident during early but not later stages of synaptic development. Gephyrin, an inhibitory scaffolding protein, was down-regulated in the somatic region, while the adhesion molecules neuroligin-2 (NL-2) and neurofascin were increased in the somatic region and/or on the dendrites. The GABAA receptor-α2 subunit (GABAAR-α2) was increased, while pre/peri-synaptic GABA clustering remained unaltered. The disproportional changes in post-synaptic adhesion molecules and GABAA receptor compared to scaffolding protein expression at the inhibitory synapses during brain inflammation are likely to cause an imbalance in GABAergic transmission. These changes were specific for the newborn neurons and were not observed when estimating the overall expression of gephyrin, NL-2, and GABAAR-α2 in the hippocampal GCL. The expression of interleukin-1-type 1 receptor (IL-1R1) on preferentially the somatic region of new neurons, often in close apposition to NL-2 clusters, may indicate a direct interaction between brain inflammation and synaptic proteins on newborn neurons. In summary, this study provides evidence that adult-born hippocampal neurons alter their inhibitory and excitatory synaptic integration when encountering an LPS-induced brain inflammation during the initial stages of synapse formation. Changes at this critical developmental period are likely to interfere with the physiological functions of new neurons within the hippocampus.
|
|
| 2. |
- Heldmann, Ursula, et al.
(författare)
-
Selective depletion of Mac-1-expressing microglia in rat subventricular zone does not alter neurogenic response early after stroke.
- 2011
-
Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 229, s. 391-398
-
Tidskriftsartikel (refereegranskat)abstract
- Ischemic stroke induces migration of newly formed neuroblasts, generated by neural stem cells in the adult rat subventricular zone (SVZ), towards the injured striatum where they differentiate into mature neurons. Stroke also leads to accumulation of microglia in the SVZ but their role for neurogenesis is unclear. Here we developed a method for selective depletion of the macrophage antigen complex-1 (Mac-1)-expressing microglia population in the SVZ by intraventricular injection of the immunotoxin Mac-1-saporin in rats. We found that the vast majority of Mac-1+ cells were Iba-1+ microglia. The Mac-1+ population was heterogeneous and included both a small proliferative pool of cells, which was not affected by middle cerebral artery occlusion (MCAO), and a larger subpopulation that changed morphologically into a semi-activated state in response to the insult. This subpopulation did not increase its expression of the phagocytic marker ED1 but exhibited high levels of triggering receptor expressed on myeloid cells-2 (TREM-2), associated with alternative microglia activation. A minor portion of the SVZ Mac-1+ cells originated from the blood early after stroke, but this macrophage population became much more substantial at later stages. Almost 80% reduction of Mac-1-expressing microglia, caused by Mac-1 saporin delivered just before and at 1week after MCAO, did not alter the numbers of newly formed neuroblasts in the striatum or their migratory distance. These findings indicate that the Mac-1-expressing microglia in the SVZ do not play a major role either for the number of neuroblasts which exit the SVZ or their migration in the striatum early following stroke.
|
|
| 3. |
- Perez-Alcazar, Marta, et al.
(författare)
-
Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3.
- 2014
-
Ingår i: Experimental neurology. - : Elsevier BV. - 1090-2430 .- 0014-4886. ; 253C, s. 154-164
-
Tidskriftsartikel (refereegranskat)abstract
- Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance.
|
|
| 4. |
- Wood, James, et al.
(författare)
-
Functional integration of new hippocampal neurons following insults to the adult brain is determined by characteristics of pathological environment.
- 2011
-
Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 229:2, s. 484-493
-
Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that following severe brain insults, chronic inflammation induced by lipopolysaccharide (LPS) injection, and status epilepticus, new dentate granule cells exhibit changes of excitatory and inhibitory synaptic drive indicating that they may mitigate the abnormal brain function. Major inflammatory changes in the environment encountering the new neurons were a common feature of these insults. Here, we have asked how the morphology and electrophysiology of new neurons are affected by a comparably mild pathology: repetitive seizures causing hyperexcitability but not inflammation. Rats were subjected to rapid kindling, i.e., 40 rapidly recurring, electrically-induced seizures, and subsequently exposed to stimulus-evoked seizures twice weekly. New granule cells were labeled 1week after the initial insult with a retroviral vector encoding green fluorescent protein. After 6-8weeks, new neurons were analyzed using confocal microscopy and whole-cell patch-clamp recordings. The new neurons exposed to the pathological environment exhibited only subtle changes in their location, orientation, dendritic arborizations, and spine morphology. In contrast to the more severe insults, the new neurons exposed to rapid kindling and stimulus-evoked seizures exhibited enhanced afferent excitatory synaptic drive which could suggest that the cells that had developed in this environment contributed to hyperexcitability. However, the new neurons showed concomitant reduction of intrinsic excitability which may counteract the propagation of this excitability to the target cells. This study provides further evidence that following insults to the adult brain, the pattern of synaptic alterations at afferent inputs to newly generated neurons is dependent on the characteristics of the pathological environment.
|
|
